The present invention relates to a process for the production of xcex2-carotene, a carotenoid that is important in the fields of medicines, feed additives and food additives and also to an intermediate of xcex2-carotene.
For the synthesis of xcex2-carotene, which is a symmetric C40 compound, there have been known a method of coupling two C19 compounds and a C2 compound, and a method of coupling two C15 compounds and a C10 compound (e.g., Helv. Chim. Acta, Vol. 39, 249 (1956) or Pure and Appl. Chem., Vol. 63, 35 (1991)). However, these methods were not always satisfactory in that they required to synthesize two different compounds having different carbon numbers and molecular structures. Methods of coupling two C20 compounds as reported in Pure and Appl. Chem., Vol. 63, 35 (1991), Japanese Patent No.2506495 or JP8-311020(Laid-Open unexamined) have also been known, however, these methods are not always practical from an industrial point of view because of multistep reactions to obtain C20 compounds, instability of intermediates, low yield of coupling reaction of said two C20 compounds, or the like.
An object of the invention is to provide a method for producing xcex2-carotene using a novel intermediate compound.
Further objects of the invention are to provide industrially advantageous two C20 compounds for producing the intermediate compound and methods for producing the two C20 compounds from an inexpensive C10 compound, linalool or geraniol in an industrially advantageous manner.
The present invention provides:
1. a process for producing a sulfone derivative of formula (1): 
xe2x80x83wherein
Ar represents an aryl group which may be substituted,
R represents a lower alkyl group and the wavy line depicted by 
xe2x80x83indicates a single bond and stereochemistry relating to a double bond bound therewith is E or Z or a mixture thereof,
xe2x80x83which comprises reacting an aldehyde derivative of formula (2): 
xe2x80x83wherein
Ar, R and the wavy line respectively have the same meanings as defined above, with a phosphonium salt of formula (3): 
xe2x80x83wherein
Ar, R and the wavy line respectively have the same meanings as defined above, X represents a halogen atom or HSO4, and
Y means an lower alkyl group or an optionally substituted phenyl group, in the presence of a base or an epoxide;
2. a sulfone derivative of formula (1) as defined above; and
3. a process for producing xcex2-carotene of formula (4): 
xe2x80x83wherein the wavy line represents the same as defined above,
which comprises reacting a sulfone derivative of formula (1) as defined above, with a base.
The present invention will be hereinafter explained in detail below.
Substituents R and Ar in the chemical formulae of (1) through (7) in the present specification will be explained first.
Examples of the lower alkyl group represented by R in the sulfone derivative (1), aldehyde derivative (2), phosphonium salt (3) and alcohol derivative (7) in the present invention include a (C1-C5) straight or branched chain alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl group, n-pentyl group, i-pentyl group, neo-pentyl group and the like. Preferred is a methyl group.
Examples of the aryl group which may be substituted represented by xe2x80x9cArxe2x80x9d include
a phenyl group and a naphthyl group, both of which may be substituted with at least one group selected from
a C1 to C6 alkyl group(e.g. a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, t-amyl, or n-hexyl group),
a C1 to C6 alkoxy group(e.g. a methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentyloxy, t-amyloxy, or n-hexyloxy group),
a halogen atom and a nitro group.
Preferred Aryl Group is a Tolyl Group.
Specific examples of the optionally substituted aryl group include a phenyl, naphthyl, o-tolyl, m-tolyl, p-tolyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-nitrophenyl, m-nitrophenyl and p-nitrophenyl group.
Next, a description will be made to the process for producing a sulfone derivative of formula (1) which comprises reacting an aldehyde derivative of formula (2) with a phosphonium salt of formula (3) in the presence of a base or an epoxide.
Specific examples of the aldehyde derivative of formula (2) include an aldehyde derivative of formula (2), wherein
Ar is a p-tolyl group and R is a methyl group, and
aldehyde derivatives of formula (2), wherein
Ar is a p-tolyl group and R represents any one of specific C2-C4 alkyl groups as described above. Further specific examples thereof include aldehyde derivatives of formula (2), wherein the p-tolyl group is replaced by other specific groups as described above for xe2x80x9cArxe2x80x9d in the above-described specific aldehyde derivatives.
The aldehyde derivative (2) can be obtained by a process as shown in Scheme 1.
In the phosphopnium salt of formula (3), a halogen atom represented by X include a chlorine atom, bromine atom and iodine atom.
Examples of the lower alkyl group represented by Y include a C1-C6 alkyl group such as a methl, ethyl, n-propyl, i-propyl, sec-butyl, n-butyl, i-butyl, n-pentyl, or the like.
Examples of the optionally substituted phenyl group represented by Y include
a phenyl group which may be substituted with a C1-C3 alkyl (e.g. a methyl, ethyl, n-propyl, or i-propyl group) or a C1-C3 alkoxy group (e.g. a methoxy, ethoxy, n-propoxy, or i-propoxy group).
Specific examples of a group of formula: PY3 in the phosphonium salt of formula (3) include triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, trihexylphosphine, triphenylphosphine, tri-(o-tolyl)phosphine and the like.
Specific examples of the phosphonium salt (3) include a phosphonium salt (3), wherein xe2x80x9cArxe2x80x9d and R have the same meaning as defined for specific examples of the aldehyde derivative of formula (2) and Y is a phenyl group and X is chlorine, and
further examples of compounds of formula (3), wherein Y represents any one of the groups as specified for Y above in place of the phenyl group above. In addition to these phosphonium salt (3), yet further examples thereof include phosphonium salts of formula (3), wherein X represents bromine, iodine or HSO4 in place of chlorine in the specified compounds above, and the like.
The amount of the phosphonium salt (3) to be used is usually 0.5 to 2.0 moles, preferably, 0.8 to 1.2 per mole of the aldehyde derivative (2).
There is no particular limitation as to the base used in the above reaction of the aforementioned phosphonium salt (3) with the aldehyde derivative (2) as long as it does not adversely affect the reaction.
Examples of the base include an alkali metal alkoxide such as potassium methoxide, potassium ethoxide, potassium n-butoxide, potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium n-butoxide, or sodium t-butoxide and an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide. An epoxide such as an ethylene oxide or 1,2-butene oxide may be used instead of the base.
The amount of the base or epoxide to be used is usually 1 to 5 moles per mol the phosphonium salt of formula (3).
Reacting of an aldehyde derivative of formula (2) with a phosphonium salt of formula (3) in the presence of a base or an epoxide is usually conducted in an organic solvent.
Examples of the solvent include
a hydrocarbon solvent such as n-hexane, cyclohexane, n-pentane, n-heptane, toluene or xylene,
a halogenated hydrocarbon solvent such as chloroform, dichloromethane, 1,2-dichloroethane, monochlorobenzene, o-dichlorobenzene or xcex1, xcex1, xcex1-trifluorotoluene,
an aprotic polar solvent such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, N,N-dimethylacetamide or hexamethylphosphoric triamide and
an ether solvent such as 1,4-dioxane, tetrahydrofuran or anisole.
The reaction may also be conducted in a two phase system of an organic solvent immiscible with water such as the hydrocarbon solvent, the halogenated hydrocarbon solvent or the like as referred to above and water.
The reaction temperature is usually in a range of about xe2x88x9210xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C.
After completion of the reaction, the reaction mixture is usually subjected to post-treatments which include optionally filtration, washing, phase separation and/or evaporation to give the sulfone derivative (1), which may be further purified by column chromatography or recrystallization, if necessary.
The phosphonium salt (3) can be obtained by a process which comprises reacting an alcohol derivative of formula (7): 
wherein Ar, R and the wavy line respectively have the same meanings as defined above, with a salt of a tertiary phosphine compound of formula: PY3 and a protonic acid, or with a tertiary phosphine compound of formula: PY3, in the presence of a protonic acid, wherein Y represents the same as defined above.
Examples of the tertiary phosphine compound include a triphenylphosphine compound of which phenyl group may be substituted with a C1-C3 alkyl or a C1-C3 alkoxy group, and a tri(C1-C6)alkylphosphine.
Specific examples of the triphenylphosphine compound include triphenylphosphine, tri-(o-tolyl)phosphine and the like.
Specific examples of said trialkylphosphine include triethylphosphine, tripropylphosphine, tributylphosphine, tripentylphosphine, trihexylphosphine and the like.
Examples of the protonic acid include hydrogen chloride, hydrogen bromide, hydrogen iodide and sulfuric acid
Examples of the salt of the tertiary phosphine compound and a protonic acid used in the above reaction include triphenylphosphine hydrochloride, triphenylphosphine hydrobromide or triphenylphosphine hydroiodide.
Examples of the protonic acid allowed to coexist with the tertiary phosphine compound include hydrogen chloride, hydrogen bromide, hydrogen iodide and sulfuric acid.
The amount of the tertiary phosphine compound or its salt with a protonic acid is usually about 0.7 to 2 moles per mol of the alcohol derivative (7). The amount of the protonic acid allowed to coexist with the tertiary phosphine compound is usually about 0.7 to 2.0 moles per mol of the alcohol derivative (7).
The reaction is usually conducted in an organic solvent, examples of which include those specified for the reaction of aldehyde derivative of formula (2) and a phosphonium derivative (3) above, and an alcohol solvent such as methanol or ethanol.
The reaction temperature is usually in a range of 10xc2x0 C. to 50xc2x0 C.
The resulting phosphonium salt (3) may be isolated after the reaction, alternatively it may be used as it is in the subsequent reaction without being isolated.
xcex2-carotene of formula (4) can be produced by a process which comprises reacting the sulfone derivative (1) with a base.
Example of the base to be used in the this reaction include an alkali metal hydroxide, an alkali metal hydride and an alkali metal alkoxide. Specific examples thereof include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium anethoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide and the like. The amount of the base is usually about 2 to 30 moles, preferably 4 to 25 moles per mol of the sulfone derivative (1).
The reaction is usually conducted in an organic solvent, examples of which include those described above for the production process of the phosphonium derivative (3) above.
The reaction temperature is usually in a range of xe2x88x9278xc2x0 C. to the boiling point of the solvent to be used.
After completion of the reaction, the reaction mixture is usually subjected to post-treatments which include optionally filtration, washing, phase separation and/or evaporation as described above to give xcex2-carotene, which may be further purified by column chromatography or recrystallization, if necessary.
Since xcex2-carotene is liable to be oxidized, said post-treatments are preferably carried out in an inert atmosphere, for example, in a atmosphere of nitrogen or argon, and an antioxidant such as BHT(di-t-butylhydroxytoluene) may be added to the reaction mixture or a solution thereof.
The alcohol derivative (7), which may be a mixture of geometrical isomers of E and Z, a racemate or an optically active isomer can be used in the present process.
The alcohol derivative (7) above can be readily synthesized from linalool or geraniol, which is available at relatively low cost, according to the route as shown by the Scheme 1 described below. A method for the synthesis of the cyclic sulfone (5) is described in JP11-222479(Laid-Open, unexamined). The sulfone (6) can be derivatized by deacylation followed by selective alkylation of a secondery alcohol group to the alcohol derivative (7), which can be oxidized to aldehyde derivative (3) as shown in the following scheme and reference examples. 